Inhibitors to HIV-I reverse transcriptase (RT) are one of the cornerstones in the treatment of AIDS patients, preventing the progression of HIV infection. The crystal structure of HIV-RT in complex with the TIBO has been solved which offers a good start to design new TIBO-like inhibitors for this protein. We are using the techniques of molecular dynamics and free energy perturbation to predict the activities of TIBO-like compounds. In particular, we are focusing on the following issues in our investigations: 1) developing and optimizing AMBER force field parameters to study this system; 2) revising and improving the CMC/MD program to predict the relative free energies of a set of ligands quickly and reliably; 3) design new TIBO-like ligands and predict their activities before synthesis.